Vast sums of money are spent annually to provide high protein feeds to agricultural animals. The productivity and growth of all animals, including humans but particularly agricultural animals, is dependent upon their ability to ingest sufficient nutrients, such as protein, carbohydrates, and minerals. Synthesis of proteins necessary for high productivity and growth requires that animals absorb sufficient amounts of peptides and amino acids into their blood streams. Of the twenty three amino acids found in the proteins of most animals, only thirteen of these can usually be synthesized in nutritionally adequate amounts by biochemical processes in the body from other substances in the diet. The ten other amino acids which can not be synthesized in sufficient quantities must therefore be ingested by the animal. (Generally, proteins are polymers formed from at least 100 amino acid residues, and peptides are oligomers comprised of from two to ten amino acids joined through amide linkages; dipeptides, tripeptides, and tetrapeptides are formed by condensation of two, three, and four amino acids, respectively.)
Therefore, it is common practice to supplement the diet of animals with nutritional sources containing especially those amino acids which can not be synthesized, or to supplement the diet with sources which can be broken down by the body to form such amino acids; otherwise, the productivity and growth of the animals may be limited in proportion to the amino acid deficiency. Obviously, however, merely increasing the available quantities of the limiting amino acids ingested by an animal does not ensure that the amino acids will ultimately be absorbed and synthesized into protein.
For example, when food is consumed by ruminants, such as sheep and cattle, it enters a complex stomach composed of four compartments, the rumen, the reticulum, the omasum, and the abomasum; the reticulum and the rumen are referred to a the reticulorumen. According to D. C. Church, food entering the reticulorumen is degraded by large populations of bacteria, protozoa, and fungi which reside there. See "Digestive Physiology and Nutrition of Ruminants," Vol. 1, O.S.U. Book Store Inc. of Corvallis, Oreg., herein incorporated by reference. The microbial degradation activity in the reticulorumen is extensive, especially in the case of carbohydrates and proteins. However, Church believed that only certain products of microbial degradation in the reticulorumen, such as volatile fatty acids and ammonia, are actually absorbed from the reticulorumen, while undegraded food residues and microorganisms pass from the reticulorumen to subsequent sections of the gastrointestinal track, where more digestion and absorption occurs.
It has also generally been accepted that dietary protein is either degraded by microorganisms in the reticulorumen, or it is passed through the reticulorumen to subsequent regions of the gastrointestinal track; dietary protein passing from the reticulorumen is then thought to be hydrolyzed to peptides and eventually to amino acids which can be readily absorbed from the intestines of the animal.
Products of dietary protein degradation in the reticulorumen were thought to be essentially utilized by microorganisms to synthesize new proteins for their cellular structures and metabolic functions; this degradation is believed to primarily result in the formation of ammonia, with some peptides and amino acids also being formed for further degradation. Peptides resulting from microbial protein hydrclysis in the reticulorumen were assumed by the prior art to be either utilized by bacteria, or degraded further to ammonia and keto acids.
It has also been widely believed that ammonia is the only nitrogen-containing product of protein degradation absorbed from the stomach. Ammonia utilization in animals is minimal, absorbed ammonia being excreted as urea.
Recent evidence suggests that large quantities of peptides are also formed in the reticulorumen, and that certain peptides are utilized by bacteria residing in the reticulorumen; other peptides formed in the reticulorumen are thought to pass through the omasum and the abomasum into the small intestine where further digestion and/or absorption occurs. The prior art concluded from this that amino acids needed by ruminant animals for protein synthesis were derived from dietary protein which had passed from the reticulorumen without degradation and from microbially generated proteins, all of which were believed to be digested in and absorbed from the small intestine and not from any part of the stomach.
Since the supply of microbially generated protein passing to the intestinal tract is limited by the rate at which microorganisms replicate in the reticulorumen, most efforts for increasing protein uptake by ruminant animals have attempted to increase the amount of undegraded protein reaching the small intestine; generally, this involved feeding animals proteins which are naturally resistant to microbial degradation, or feeding animals proteins which were treated with compounds, such as formaldehyde or tannin, to decrease degradation in the reticulorumen.
Wu et al., in U.S. Pat. No. 4,595,584, herein incorporated by reference, state that the natural nutritional balance of ruminant animals was primarily a function of the microbial composition and population, and that the rate of meat, wool, flesh, or milk production could be increased if sources of growth limiting essential amino acids, and/or medicaments were protected from alteration by microorganisms residing in the rumen; the protected compounds are then thought to become available for direct absorption by the animal later in the gastrointestinal track. Therefore, Wu et al. formed pellets for oral administration which had a core material containing necessary nutrients or medicaments, and the cores . were coated, e.g. with an enteric coating, to protect them while in the rumen; the coating was designed to dissolve in the acidic conditions of the abomasum so that the core material could be broken down into a form which the organisms were capable of utilizing.
Despite the widely held belief that amino acid and peptide absorption only occurs further along in the gastrointestinal track than the stomach, it has been ascertained experimentally that certain peptides are not only absorbed into the blood stream through the lining of ruminant stomachs, but some peptides are apparently absorbed more efficiently through the stomach lining. It is believed this absorption is primarily carried out through the lining of the reticulorumen and omasum, rather than the abomasum, because of the large absorptive area in the former compartments. This indicates that prior art attempts to protect protein and medicament containing feeds from degradation in the stomach may actually be counterproductive. Since any peptides in such coated feeds which are capable of being absorbed through the stomach lining are prevented from doing so, feeds protected from microbial degradation may result in reduced utilization of dietary proteins. Further, due to the increased quantity of amino acids in the small intestine resulting from coated feeds, competition for absorption is increased and the efficiency of amino acid absorption may be substantially decreased.
Optimal dietary protein formulations for high producing . ruminants, such as beef cattle and lactating dairy cattle, have not been realized using protected feeds; this is evident from the substantial amounts of waste products from dietary protein excreted in the urine and feces of animals fed prior art feeds, which indicates that optimal mixtures of protein and amino acids are not being presented for digestion and utilization.
It is believed that methionine and lysine are the principle limiting amino acids in ruminant diets, with histidine, phenylalanine, and threonine also playing important limiting roles. Adding these amino acids in synthetic form to ruminant diets has not been effective as the amine acids are destroyed by the microbial population in the reticulorumen, making them unavailable to the animal. Peptides which contain these amino acids and which also resist microbial degradation in the reticulorumen long enough to be absorbed from the stomach, will result in substantial improvements in animal productivity at reduced cost by ensuring that the animals uptake the proper amount of essential amino acids. A further benefit of peptide absorption through the stomach is a reduction in the metabolic energy expenditure required for the absorption of nutrients; since the energy lost in transporting a single amino acid across an absorptive membrane is about the same as transporting a peptide containing multiple amino acid residues, peptide absorption would reduce the energy required to absorb the amino acid needs of the animal. (Absorbed peptides would subsequently be hydrolyzed to their constituent amino acids for use in protein synthesis.)
Thus, there is a need for compositions containing peptides which are capable of absorption from the stomach in order to assure adequate uptake of necessary amino acids. Further, there is a need for methods of treating dietary deficiencies in animals and/or supplying necessary nutrients to animals which does not require coating or other treatment of the nutrients contained therein to prevent microbial degradation or breakdown in the stomach.
While normal or conventional dietary compositions for animals may, and presumably do, contain some amount of peptides, given the conviction of prior workers that such ingested peptides would be degraded in the stomach to nutritionally useless by-products or at the least would not undergo absorption until reaching the intestines, at which point the much larger amount of true protein would release its nutritional components at far more significant levels compared to what might be contributed by the peptides, it is hardly surprising that the possible presence of peptides in the feed was ignored, and not even measured in typical analyses of dietary compositions. Under such circumstances, there was no reason for modifying the normal diet to augment whatever starting amount of peptide might have naturally been present, and even less reason to emphasize the selection of peptides characterized by residues of especially valuable or essential amino acids. Further, there was no incentive to take peculiar advantage of the simple structure of lower oligomeric peptides to synthesize special peptides having enhanced levels of such amino acids. However, in this manner the present invention overcomes specific dietary deficiencies in particular animals on the one hand, while on the other, the diet for normal animals can be tailored to optimize the function of the animal in producing meat, milk, offspring, etc. cl SUMMARY OF THE INVENTION
Once the fundamental phenomena of the invention are comprehended, the formulation of suitable feed compositions will be immediately obvious to those knowledgeable in the field so that detailed discussion becomes unnecessary; suitable compositions contain peptides, or peptide derivatives, or peptide precursors that release peptides within the stomach by gastric action, the peptides being capable of absorption into the blood stream through the lining of the stomach of animals ingesting them to supply particular nutrients to ruminants and other animals. In a preferred embodiment, feed compositions are modified to incorporate significant amounts of peptides containing one or more amino acid residues in which an animal is deficient. In formulating preferred feed compositions, the peptides selected are those which have been determined to be absorbed in substantial amounts through the lining of the stomach. Synthetic peptides may be used, or feed stocks containing proteins and polypeptides which break down to form peptides which can be absorbed through the stomach lining may be used.
As an alternative embodiment, the possibility exists for complexing peptides capable of absorption into the blood stream through the stomach lining with medicaments or mineral containing compounds which an animal requires, and feed compositions containing these peptide derivatives are fed to nutrient-deficient animals or animals suffering from an illness for which the medicament is effective. In another specific embodiment, compositions are formulated to incorporate peptides or peptide derivatives that contain proline, phenylalanine, or glycine, that appear to be preferentially absorbed in the stomach as well at least one other less readily absorbable amino acid or nutrient in which an animal is deficient in order to facilitate the absorption of the latter into the blood stream through the lining of the stomach.
In a preferred process for providing nutrients to ruminants, or for treating dietary deficiencies in ruminants, feed compositions are formulated which contain increased amounts of peptides known to be absorbed into the blood stream through the lining of the stomach. Preferred peptides contain proline, glycine, or phenylalanine, and have no more than two to four amino acid residues; preferably, the peptides are supplied to animals in concentrations greater than can be found in any conventional feed source. Natural sources containing sufficient concentrations of desired peptides which can be absorbed through the stomach may also be used in a preferred method of supplying nutrients and treating dietary deficiencies.
Thus, it is a primary object of the present invention to provide feed compositions which contain peptides that are capable of absorption into the blood stream through the lining of the stomach.
It is a further object of the present invention to provide feed compositions for ruminants which contain peptides that resist microbial degradation in the reticulorumen and which are absorbed into the blood stream from the stomach.
It is yet another object of the present invention to provide a method for the treatment of dietary deficiencies which involves modifying the dietary intake of animals to incorporate increased levels of peptides or peptide derivatives providing essential nutrients for absorption in the stomach of such animals and into the blood stream thereof.